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Background: SARS-CoV-2 antibody levels have been proposed as a correlate of protection (CoP) from infection. Yet, large-scale prospective studies of cost-effective scalable antibody measures as predictors of infection under real-world conditions are limited. We examined whether antibody levels measured using high-throughput variant-specific SARS-CoV-2 anti-spike immunoglobulin G (IgG) and ACE2-neutralization assays correlate with cell-based neutralizing antibody (NAb) measurements, and whether they can serve as a reasonable CoP from SARS-CoV-2 infection., Methods: We conducted a large, institutional cohort study between January 2022 and March 2023. Participants (n=2,513) provided dried blood spot (DBS) samples for assessment of anti-spike IgG and ACE2 inhibition levels using high-throughput assays. Comparison with authentic cell-based SARS-CoV-2 NAb assays was conducted using serum samples (n=105). Associations between antibody levels and risk of infection were evaluated., Findings: Correlation between serum and DBS sampling, and cell-based neutralizing and high-throughput antibody binding assays, was high for both anti-spike IgG and ACE2 neutralization, though the degree of correlation varied by variant. Longitudinal evaluation suggested both DBS-based IgG and ACE2 inhibition levels were anticorrelated with infection risk, with higher sensitivity noted for ACE2 inhibition and variant-matched measures. Both IgG and ACE2 inhibition levels decreased over time, with more durable responses observed in participants whose most recent priming event was infection versus vaccination., Interpretation: Findings suggest that variant-specific SARS-CoV-2 antibody levels may be a useful CoP for infection, which has important implications for vaccination recommendations and evaluating infection risk. High-throughput assays measured via DBS may have utility in timing of boosters, either at the population or an individual level., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)